Addressing the interplay between apoptosis and glucose metabolism in liver cirrhosis and hcc

Introduction: Pro-inflammatory signalling in the liver promotes the appearance of a metabolic phenotype that involves the transition from mitochondrial respiration to aerobic glycolysis. It was demonstrated that this metabolic shift occurs during the transition from healthy and early stage of liver injury (NAFLD/NASH, ALD to late stage of disease (i.e. cirrhosis), and further escalates during HCC development.1,2This metabolic signature enables dividing cells to satisfy anabolic and energetic needs for biomass production and to suppress apoptotic signalling, which is consistent with increased compensatory hepatic cell proliferation typical of cirrhotic and HCC livers. However other studies in contrast have suggested that hepatocytes are unable to sustain glycolysis during late stage of chronic liver disease.3 Method: We used unbiased gene expression analyses of microarray datasets to investigate the expression of glycolytic genes in cirrhotic and HCC livers and correlated their expression with patient outcome. Furthermore, by using a combination of in vitro and in vivo analyses we have characterised the abilities of a novel anti-apoptotic gene to regulate aerobic glycolysis in liver cirrhosis and HCC. Results: mRNA profiling showed significantly higher expression of glycolytic transcripts in cirrhotic and HCC livers compared to normal quiescent livers (P < 0.05). Up regulation of Glut1, Hk1, Hk2, G6PI, and PFKLwas seen in HCC livers compared to their adjacent non-tumour tissues (P < 0.001). Notably, expression of enzymes regulating mitochondrial activity (Pdha, Pdk) was unchanged between non-tumour tissues and late stage of HCC. Moreover, up regulation of a novel anti-apoptotic gene positively correlated with increased expression of glycolytic transcripts in a group of cirrhotic patients prospectively classified as poor prognosis based on HCC development, and promotes the aerobic glycolysis of hepatoma cells. Conclusion: In summary, our findings delineate a putative link between aerobic glycolysis and suppression of apoptosis that is an important part of the progression of cirrhosis to HCC. The identification of the mechanism regulating this link may lead to design new therapeutic strategies for human liver disease

Inhibition of mapk signalling promotes cell cycle arrest and sensitises intrahepatic cholangiocarcinoma cells to chemotherapy

Introduction: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy, accounting for approximately 15% of cases of primary liver cancer. Although new treatments have increased survival for many other cancers, including the more common primary hepatocellular carcinoma, treatment strategies and survival for patients with ICC have seen little improvement. Our previous studies suggest that the mitogen-activated protein kinase (MAPK) signalling plays a central role in the regulation of cell proliferation in human ICC. However the molecular mechanisms are poorly understood. In this study, we aim to explore whether inhibition of the MAPK pathway and its downstream effectors enhances the sensitisation of ICC cells to the chemotherapeutic agent cisplatinum. Method: We used a combinatorial approach of immunohistochemical and gene expression analyses to investigate the expression of MAPK-related genes in ICC tumours. Furthermore, by using in-vitroand in-vivoanalyses we have characterised the function of a novel MAPK downstream effector in ICC cells. Results: The expression of MAPK signalling was determined by immunohistochemical staining in tumour samples from a cohort of 14 ICC patients. High expression of phospho-activated MAPK was observed in 71.4% (10/14) of ICC cases as compared with surrounding nontumour tissue. Likewise, expression of JDP, a downstream effector of the MAPK signalling, was scored as high intensity in 64.3% (9/14). Strikingly, elevated expression of JDP transcripts was also observed in two independent cohorts of human ICC (n = 149 and n = 109 per group, respectively) compared to surrounding normal liver tissue. Consistent with the in-vivo analyses of human samples, immunoblotting analyses showed constitutive activation of MAPK and expression of JDP in ICC-derived cells (i.e. SG231, CCLP-1 and HuCCT1). Using loss-of-function analyses, we demonstrates that knockdown of JDP in ICC-derived cells resulted in cell cycle arrest and reduced expression of cell cycle regulators (i.e. cyclins), and had minimal effect on apoptosis. Chemical inhibition of JDP significantly sensitises ICC-derived cells to cisplatinum (P < 0.001). Conclusion: These results demonstrate that enhanced activation of MAPK signalling is important for ICC cell proliferation and suggest that targeting its downstream effectors is a potential therapeutic strategy for ICC

Wing Patterns in the Mist

Arnaud Martin is with University of California Irvine, Durrell D. Kapan is with University of Hawaii at Manoa, Lawrence E. Gilbert is with UT Austin.The aesthetic appeal of butterfly wing patterns has been costly to their status as a tool of fundamental scientific inquiry. Thus, while mimetic convergence in wing patterns between edible “Batesian” mimics and distasteful models, or between different distasteful “Müllerian” mimics (species that cooperate to educate predators) has long been the subject of genetic analysis [1] and field experiments [2], most biology text books confine mimicry to sections on striking adaptations without applying these examples to broader topics of evolution. Meanwhile, the study of color patterns in animals, often tucked into the same sections of texts, is undergoing a revolution in this age of evo-devo and genomics [3]. Among insect models for studying color pattern, the genus Heliconius is gaining the attention of an ever-widening audience.Biological Sciences, School o

Eccentric Exercise Activates Novel Transcriptional Regulation of Hypertrophic Signaling Pathways Not Affected by Hormone Changes

Unaccustomed eccentric exercise damages skeletal muscle tissue, activating mechanisms of recovery and remodeling that may be influenced by the female sex hormone 17β-estradiol (E2). Using high density oligonucleotide based microarrays, we screened for differences in mRNA expression caused by E2 and eccentric exercise. After random assignment to 8 days of either placebo (CON) or E2 (EXP), eighteen men performed 150 single-leg eccentric contractions. Muscle biopsies were collected at baseline (BL), following supplementation (PS), +3 hours (3H) and +48 hours (48H) after exercise. Serum E2 concentrations increased significantly with supplementation (P<0.001) but did not affect microarray results. Exercise led to early transcriptional changes in striated muscle activator of Rho signaling (STARS), Rho family GTPase 3 (RND3), mitogen activated protein kinase (MAPK) regulation and the downstream transcription factor FOS. Targeted RT-PCR analysis identified concurrent induction of negative regulators of calcineurin signaling RCAN (P<0.001) and HMOX1 (P = 0.009). Protein contents were elevated for RND3 at 3H (P = 0.02) and FOS at 48H (P<0.05). These findings indicate that early RhoA and NFAT signaling and regulation are altered following exercise for muscle remodeling and repair, but are not affected by E2

IgG responses to the gSG6-P1 salivary peptide for evaluating human exposure to Anopheles bites in urban areas of Dakar region, Sénégal

<p>Abstract</p> <p>Background</p> <p>Urban malaria can be a serious public health problem in Africa. Human-landing catches of mosquitoes, a standard entomological method to assess human exposure to malaria vector bites, can lack sensitivity in areas where exposure is low. A simple and highly sensitive tool could be a complementary indicator for evaluating malaria exposure in such epidemiological contexts. The human antibody response to the specific <it>Anopheles </it>gSG6-P1 salivary peptide have been described as an adequate tool biomarker for a reliable assessment of human exposure level to <it>Anopheles </it>bites. The aim of this study was to use this biomarker to evaluate the human exposure to <it>Anopheles </it>mosquito bites in urban settings of Dakar (Senegal), one of the largest cities in West Africa, where <it>Anopheles </it>biting rates and malaria transmission are supposed to be low.</p> <p>Methods</p> <p>One cross-sectional study concerning 1,010 (505 households) children (n = 505) and adults (n = 505) living in 16 districts of downtown Dakar and its suburbs was performed from October to December 2008. The IgG responses to gSG6-P1 peptide have been assessed and compared to entomological data obtained in or near the same district.</p> <p>Results</p> <p>Considerable individual variations in anti-gSG6-P1 IgG levels were observed between and within districts. In spite of this individual heterogeneity, the median level of specific IgG and the percentage of immune responders differed significantly between districts. A positive and significant association was observed between the exposure levels to <it>Anopheles gambiae </it>bites, estimated by classical entomological methods, and the median IgG levels or the percentage of immune responders measuring the contact between human populations and <it>Anopheles </it>mosquitoes. Interestingly, immunological parameters seemed to better discriminate the exposure level to <it>Anopheles </it>bites between different exposure groups of districts.</p> <p>Conclusions</p> <p>Specific human IgG responses to gSG6-P1 peptide biomarker represent, at the population and individual levels, a credible new alternative tool to assess accurately the heterogeneity of exposure level to <it>Anopheles </it>bites and malaria risk in low urban transmission areas. The development of such biomarker tool would be particularly relevant for mapping and monitoring malaria risk and for measuring the efficiency of vector control strategies in these specific settings.</p

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration